Models of blood coagulation
Department of Biochemistry, 208 South Park Drive, Suite 2, University of Vermont, College of Medicine, Colchester, VT 05446, USA. Blood Cells Molecules and Diseases
(Impact Factor: 2.65).
05/2000; 36(2):108-17. DOI: 10.1016/j.bcmd.2005.12.034
Our research aims to provide quantitatively transparent, biologically realistic descriptions of the processes involved in hemostasis which will permit predictions of the behavior of the coagulation system in normal and pathologic states. We use four models of coagulation: (1) numerical approximations of the tissue factor (Tf) pathway of thrombin generation based upon mechanism and dynamics; (2) Tf activation of the "blood coagulation proteome" from isolated cells and proteins; (3) Tf activated contact pathway inhibited whole blood in vitro; and (4) blood shed from standardized microvascular wounds in vivo. The results from these models are integrated in interactive assessments aimed at achieving convergence of biochemical rigor and biological authenticity. Microvascular injury is the most biologically secure but least accessible to mechanistic study. Numerical models while quantitatively transparent are biologically limited. By the integrated analyses of all four models, we establish observations which require inclusion or discovery of new parameters to achieve mechanistically interpretable biological reality. Discoveries made in this fashion have included thrombin's role in the initiation phase, TFPI/ATIII/APC synergy interactions, rfVIIa in fVII deficiency, the roles of fVIII and fIX in the Tf reaction, and the cleavage of fIX by fXa membrane. Ideally, our results will provide descriptions which predict the behavior of the biological blood coagulation system under normal and pathologic conditions.
Available from: Md. Ali
- "It provides a " hemostatic envelope " in order to limit bleeding after vessel injury. Aberrant TF expression within the vasculature can initiate lifethreatening thrombosis in diseases like sepsis, atherosclerosis or even in cancer (Mackman 2004; Mann et al. 2006). Initiation of the coagulation cascade via exposure of TF to blood and the formation of TF/FVIIa complex are essential events for hemostasis and are initial procuagulant signal in thrombosis (Wolberg and Mast 2012). "
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ABSTRACT: Tissue Factor (TF), a membrane bound glycoprotein, is the cellular initiator of the protease blood coagulation cascade. TF is a component of tissue factor/factor VII (TF/FVII) complex which plays key roles in extrinsic coagulation pathway. According to the traditional view of blood coagulation, although the initial phase of coagulation is triggered by the extrinsic pathway, the amplification of the coagulation cascade is triggered by the intrinsic pathway. Emerging experimental evidences show a broad range of biological functions of TF including hemostasis, thrombosis, hypercoagulability etc. In addition to the role of TF as an initiator of coagulation cascade, TF is also involved in many cancer-related processes like tumor growth, angiogenesis, metastasis etc. It is now widely recognized that a strong correlation exists between TF expression and breast cancer and plasma TF concentration has been found to be up-regulated in primary and recurrent breast cancer patients. TF-induced thrombin can activate several members of the protease activated receptor (PAR) family. Expression of protease activated receptor 1 (PAR1) is both required and sufficient to promote growth and invasion of breast carcinoma cells. Like PAR1, protease activated receptor 2 (PAR2) has also been found to play a critical role in breast cancer cell migration and invasion. Thus, TF plays a very crucial role in breast cancer progression. This review focuses on the role of TF in breast cancer progression based on the evidences available. Better understanding the role of TF in breast cancer will provide considerable clinical benefits associated with breast cancer treatment.
Available from: Alexej Victorovich Sokolov
- "ProT is the physiological precursor of mature α-thrombin (α-T) and is composed of F1 and F2 regions, and the protease domain . Pre2 is the shortest precursor of α-thrombin, differing from the mature enzyme only for having the Arg15-Ile16 bond intact (α-T numbering) . The recently solved crystallographic structures of ProT  and Pre2  reveal that , compared to α- T, major perturbations occur in the Na + -binding site, in the activation domain and in the insertion loops surrounding on the catalytic cleft. "
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ABSTRACT: Human ceruloplasmin (CP) is a multifunctional copper-binding protein produced in the liver. CP oxidizes Fe(2+) to Fe(3+), decreasing the concentration of Fe(2+) available for generating harmful oxidant species. CP is also a potent inhibitor of leukocyte myeloperoxidase (MPO) (Kd=130nM), a major source of oxidants in vivo. Rheumatoid arthritis (RA) is an inflammatory autoimmune disease affecting flexible joints and characterized by activation of both inflammatory and coagulation processes. Indeed, the levels of CP, MPO and thrombin are markedly increased in the synovial fluid of RA patients. Here we show that thrombin cleaves CP in vitro at (481)Arg-Ser(482) and (887)Lys-Val(888) bonds, generating a nicked species that retains the native-like fold and the ferroxidase activity of the intact protein, whereas the MPO inhibitory function of CP is abrogated. Analysis of the synovial fluid of 24 RA patients reveals that CP is proteolytically degraded to a variable extent, with a fragmentation pattern similar to that observed with thrombin in vitro, and that proteolysis is blocked by hirudin, a highly potent and specific thrombin inhibitor. Using independent biophysical techniques, we show that thrombin has intrinsic affinity for CP (Kd=60-270nM), independently of proteolysis, and inhibits CP ferroxidase activity (KI=220±20nM). Mapping of thrombin binding sites with specific exosite-directed ligands (i.e. hirugen, fibrinogen γ'-peptide) and thrombin analogues having the exosites variably compromised (i.e. prothrombin, prethrombin-2, βT-thrombin), reveals that the positively charged exosite-II of thrombin binds to the negatively charged upper region of CP, while the protease active site and exosite-I remain accessible. These results suggest that thrombin can exacerbate inflammation in RA by impairing via proteolysis the MPO inhibitory function of CP and by competitively inhibiting CP ferroxidase activity.
Copyright © 2015. Published by Elsevier Inc.
Available from: Perry JJ van Genderen
- "This TFPI-Xa complex subsequently binds to the TF-VIIa complex, thereby inhibiting further activity of coagulation factor VIIa. TFPI present in plasma is active, but present in low concentrations and only able to delay the coagulation cascade. TFPI can be released by degranulation of activated platelets and/or from the endothelium by heparin and thereby regulate TF activity , . The presence of heparin-like molecules on the outer surface of adult schistosomes suggests that the parasite may stimulate the release and local accumulation of TFPI from the endothelium, although this has not been confirmed. "
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ABSTRACT: Schistosomes, parasitic flatworms that cause the tropical disease schistosomiasis, are still a threat. They are responsible for 200 million infections worldwide and an estimated 280,000 deaths annually in sub-Saharan Africa alone. The adult parasites reside as pairs in the mesenteric or perivesicular veins of their human host, where they can survive for up to 30 years. The parasite is a potential activator of blood coagulation according to Virchow's triad, because it is expected to alter blood flow and endothelial function, leading to hypercoagulability. In contrast, hepatosplenic schistosomiasis patients are in a hypocoagulable and hyperfibrinolytic state, indicating that schistosomes interfere with the haemostatic system of their host. In this review, the interactions of schistosomes with primary haemostasis, secondary haemostasis, fibrinolysis, and the vascular tone will be discussed to provide insight into the reduction in coagulation observed in schistosomiasis patients.
Interference with the haemostatic system by pathogens is a common mechanism and has been described for other parasitic worms, bacteria, and fungi as a mechanism to support survival and spread or enhance virulence. Insight into the mechanisms used by schistosomes to interfere with the haemostatic system will provide important insight into the maintenance of the parasitic life cycle within the host. This knowledge may reveal new potential anti-schistosome drug and vaccine targets. In addition, some of the survival mechanisms employed by schistosomes might be used by other pathogens, and therefore, these mechanisms that interfere with host haemostasis might be a broad target for drug development against blood-dwelling pathogens. Also, schistosome antithrombotic or thrombolytic molecules could form potential new drugs in the treatment of haemostatic disorders.
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